Management of High Altitude Pathophysiology

Management of High Altitude Pathophysiology

First Edition

Kshipra Misra

Priyanka Sharma

Anuja Bhardwaj

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Preface

Section I: Human Performance at High Altitude

Chapter 1: High Altitude and Hypoxia

Abstract

1.1 Introduction

1.2 High Altitudes: Worldwide Scenario

1.3 High Altitudes Environment and Hypoxia

1.4 Hypobaric Hypoxia and Physiology

1.5 Conclusion

Chapter 2: High Altitude Ailments: Causes and Effects

Abstract

Acknowledgments

2.1 Introduction

2.2 High-Altitude Ailments

2.3 Conclusions

Section II: Herbal Therapeutics for High Altitude Problems

Chapter 3: Hippophae sp.: A Boon for High-Altitude Maladies

Abstract

Acknowledgments

3.1 Introduction

3.2 History and Traditional Usage

3.3 Botanical Description and Natural Distribution

3.4 Hippophae Species

3.5 Chemical Constituents of H. rhamnoides

3.6 Bioactivities of H. rhamnoides

3.7 Health and Nutritional Products From H. rhamnoides

3.8 Conclusions

Chapter 4: Valeriana sp.: The Role in Ameliorating High-Altitude Ailments

Abstract

Acknowledgements

4.1 Introduction

4.2 Description of the Plant

4.3 Geographical Distribution and Habitat

4.4 Active Constituents in V. wallichii

4.5 Biological Activities of V. wallichii

4.6 Applications of V. wallichii in Improving Health at High Altitudes

4.7 Conclusions

Chapter 5: Rhodiola sp.: The Herbal Remedy for High-Altitude Problems

Abstract

Acknowledgments

5.1 Introduction

5.2 Geographical Distribution of Rhodiola sp.

5.3 Botanical Classification of Rhodiola sp.

5.4 Bioactive Components in Rhodiola sp.

5.5 Pharmacological and Medicinal Importance of Rhodiola sp.

5.6 Conclusions

Chapter 6: Cordyceps sp.: The Precious Mushroom for High-Altitude Maladies

Abstract

Acknowledgments

6.1 Introduction

6.2 Vegetation at High Altitude

6.3 Origin and Geographical Distribution of C. sinensis

6.4 Life Cycle of C. sinensis

6.5 Major Bioactive Constituents Isolated From C. sinensis and Their Ameliorating Effects

6.6 Cultivation of C. sinensis

6.7 Products Based on C. sinensis

6.8 Studies Showing Ameliorating Effects

6.9 Conclusion

Chapter 7: Ganoderma sp.: The Royal Mushroom for High-Altitude Ailments

Abstract

Acknowledgment

7.1 Introduction

7.2 History of Ganoderma

7.3 Taxonomy and Geographical Distribution

7.4 Metabolite Profile of G. lucidum

7.5 Pharmacological Effects of G. lucidum

7.6 Conclusions

Chapter 8: Curcuma sp.: The Nature's Souvenir for High-Altitude Illness

Abstract

Acknowledgments

8.1 Introduction

8.2 General Description of Curcuma Species

8.3 Different Species of Curcuma Genus

8.4 Medicinal Implications of Curcuma Species

8.5 Curcumin as a Therapeutic Against Hypoxia

8.6 Conclusion

Chapter 9: Characterization Techniques for Herbal Products

Abstract

Acknowledgments

9.1 Introduction

9.2 Characteristics of HA Himalayan Medicinal Plants

9.3 Extraction, Isolation, and Characterization of Bioactive Compounds From Herbal Sources

9.4 Multihyphenated Characterization Techniques

9.5 Conclusions

Section III: Nonherbal Therapeutics for High-Altitude Illness

Chapter 10: Allopathic Remedies

Abstract

Acknowledgment

10.1 Introduction

10.2 Allopathic Remedies for High-Altitude Ailments

10.3 Conclusions

Chapter 11: Homeopathic Remedies

Abstract

Acknowledgment

11.1 Introduction

11.2 The Origin and Principals of Homeopathy

11.3 Worldwide Prevalence and Further Scope of Homeopathy

11.4 Homeopathic Remedies for High-Altitude Ailments

11.5 Conclusions

Chapter 12: Nanoformulations: A Novel Approach Against Hypoxia

Abstract

Acknowledgment

12.1 Introduction

12.2 Emergence of Nanotechnology

12.3 Nanomaterials

12.4 Nanoformulations

12.5 Nanoformulations for Hypoxia

12.6 Nanoformulations for Hypobaric Hypoxia

12.7 Prospective Nanoformulations for High-Altitude Pathophysiologies

12.8 Conclusions

Chapter 13: Electrochemical Immunobiosensors for Point-of-Care Detection of Hypoxia Biomarkers

Abstract

Acknowledgment

13.1 Introduction

13.2 Electrochemical Immunosensor for SOD1

13.3 LABVIEW-Based Virtual Instrumentation for Nitric Oxide and Cytochrome c Biosensing

13.4 ARM Microcontroller Based Portable Electrochemical Analyzer for Nitrite Biosensing

13.5 Conclusion

Section IV: Nonmedical Therapies for High Altitude Ailments

Chapter 14: Performance Enhancement Through Physical Activity at High Altitudes

Abstract

Acknowledgments

14.1 Introduction

14.2 Defining Altitude

14.3 Environmental Factors Affecting Physical Activity at High Altitudes

14.4 Human Habitability and Physical Activity at High Altitudes

14.5 Enhancing Performance at HA: An Ergonomics Overview

14.6 Conclusions

Chapter 15: Yogic Practices for High-Altitude Ailments

Abstract

15.1 Introduction

15.2 Yoga and Its Evolution

15.3 Benefits of Yoga (Asana, Pranayama, and Meditation)

15.4 High-Altitude Ailments and Yoga

15.5 Conclusions

Index

Copyright

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Dedication

Dedicated

To

Dr. B. B. Sarkar

for his altruistic and inspirational services to Indian soldiers.

Contributors

Rajesh Arora       Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Murugesan Balamurugan       Department of Chemistry, Biomedical Research Lab, VHNSN College (Autonomous), Virudhunagar, India

Anuja Bhardwaj       Chemistry Division, Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Jonathan C. Claussen       Mechanical Engineering, Iowa State University, Ames, IA, United States

Arul J. Duraisamy       Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, United States

Shefali Gola       Department of Basic and Applied Sciences, School of Engineering, GD Goenka University, Haryana, India

Chandran Karunakaran       Department of Chemistry, Biomedical Research Lab, VHNSN College (Autonomous), Virudhunagar, India

Deepti Majumdar       Ergonomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Preenon Majumdar       Kalinga Institute of Medical Sciences, Bhubaneshwar, India

Dhurjati Majumdar       Defence Research and Development Organization, New Delhi, India

Manimaran Manickam       Research and Development, PathGene Healthcare Private Limited, Tirupathi, India

Jigni Mishra       Chemistry Division, Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Kshipra Misra       Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Mamta Pal       Division of Forensic Science, School of Basic and Applied Sciences, Galgotias University, Greater Noida, India

Syed Rahamathulla       Research and Development, PathGene Healthcare Private Limited, Tirupathi, India

Rakhee       Department of Chemistry, University of Delhi, Delhi, India

Paulraj Santharaman       Department of Chemistry, Biomedical Research Lab, VHNSN College (Autonomous), Virudhunagar, India

Priyanka Sharma       Cardiorespiratory Department, Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Raj K. Sharma       Department of Chemistry, University of Delhi, Delhi, India

Sushil Kumar Singh       Functional Materials Group, Solid State Physics Lab, Defence Research and Development Organization, Timarpur, India

Preface

Kshipra Misra ; Priyanka Sharma ; Anuja Bhardwaj

Towering, majestic mountains, with their snow-capped peaks and rarefied atmosphere, have always fascinated, inspired, and attracted people. Many people travel to and stay at high altitudes for varying lengths of time, either for recreation (such as tourists and mountaineers) or for work (such as armed forces), exposing them to hypoxia and the entailed risk of acute mountain sickness. Such an exposure, at times, can lead to high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE) that could cause serious health complications. Every person, regardless of age, gender, or physical characteristics, exposed to high altitudes is vulnerable to high-altitude-induced hypobaric hypoxia, which is an irreversible, lifelong condition, imposing severe physiological distress. Hypoxia is caused by rarefied atmosphere at high altitudes, reflected in low barometric pressure, and the consequent low oxygen density in inhaled air compared to the oxygen density at sea level. Oxygen density progressively declines with the increasing altitude, causing correspondingly higher stress to the human physiological systems, because a steady, uninterrupted supply of oxygen is essential for normal functioning of mitochondrial metabolism.

Given the almost inevitable physiological consequences of hypoxia, it is a major challenge to maintain the normal level of functional performance of people who live and work at high altitude. Though the instinctive adaptation of the physical and mental capabilities of human beings in the face of such a harsh working environment could be viewed as mitigating the risk to an extent, that is not optimal, and people in that environment do become the victims of the deleterious impact of hypoxia to varying degrees. With a view to combating the multiple health complications arising from hypobaric hypoxia, several therapies have been developed over the years, and some of them are being practiced worldwide.

The main objective of writing this book is to provide the readers a holistic view of prevalent environmental conditions at high altitudes, including hypoxia and low temperatures, their effects on human physiology, and the various measures adopted for the effective management of the pathophysiological impact of that environment. We have tried to present our views on the current and emerging scenario in the field of management of high-altitude pathophysiology. The scheme of presentation in the book is summarized below.

Section I presents an overview of the unique environmental features observed at the high altitudes, and their physiological effects on human beings.

Sections II and III highlight herbal and nonherbal therapeutics, respectively, being practiced and researched for the management of high-altitude pathophysiology. Each chapter of these sections seeks to present comprehensively the current state of research in this area.

The role of exercise and yogic interventions has been found to be invaluable in maintaining physical wellbeing at the high altitudes. This aspect forms the subject matter of Section IV and is discussed in detail in its two chapters.

We would like to thank all those, too numerous to name here, who have been a source of inspiration for initiating this project, and those who helped us in completing this book. We are especially grateful to Dr. A. K. Datta, former Chief Controller, R& D, Defence Research & Development Organisation, India for his enduring support and encouragement all along. The authors are thankful to the Director of Defence Institute of Physiology and Allied Sciences (DIPAS) for granting permission to write the book. We would like to thank all the authors who readily agreed to contribute their research findings to this book and without whose support this book could not have materialized. We are also grateful to Elsevier publishers for providing us an opportunity to publish this book. Last but not the least, we are grateful to the Indian soldiers whose lives inspired us to do something, however small and indirect, toward improving their wellbeing in the midst of their harsh working conditions at high altitudes.

This small effort in compiling current research in the area of high-altitude pathophysiology, we hope, also will throw some light on the direction of further research needed in this field.

Section I

Human Performance at High Altitude

Chapter 1

High Altitude and Hypoxia

Priyanka Sharma⁎; Kshipra Misra†    ⁎ Cardiorespiratory Department, Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

† Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Abstract

Prolonged stay at high altitudes, either as a part of a personal adventure or as a member of a country's defense force, adds to existing stressful dimensions of this world. War operations at high altitudes force lowlanders into uninhabited mountain regions, making the study of this alien environment more important. Hypoxia is the most significant and connatural factor of such an environment. Hypoxia, or rarefied atmosphere with low oxygen availability, can affect a person's physical and mental performances. Although the effect of hypoxia is seen at an altitude of 1500 m, high altitudes generally are considered to be higher than 3000 m. High-altitude hypoxia persistently affects everyone because oxygen is even more essential than food and water. This chapter introduces readers to the concepts of high altitudes, the worldwide scenario of high altitudes, and the related hypoxia (hypobaric hypoxia).

Keywords

High altitude; Hypoxia; Oxygen; Hypobaric

List of Abbreviations

mmHg millimeters of mercury

PO2 partial pressure of oxygen in ambient air

1.1 Introduction

Altitude has different meaning based on the context in which it is used. In general, altitude is vertical distance between a reference datum and a point or object. The term altitude, also called true altitude, commonly is used to mean the height of a location above sea level. The distance of a point from the ground below is sometimes called absolute altitude, as described in ISO 6709:2008(en) preview (ISO, 2008). Altitude is related to air pressure and can be determined by measuring air pressure with an altimeter. As altitude rises, air pressure drops because of two reasons: First, Earth's gravitational pull keeps air as close as possible to its surface. Second, the number of molecules in the air decreases as the altitude increases, making the air less dense. Less dense air also is cooler because fewer molecules have much less chance to collide with each other. Altitude could be further divided based on the distance from the sea level (Fig. 1.1). Regions on the Earth’s surface (or in its atmosphere) that are high above mean sea level are referred to as high altitudes. High altitudes sometimes are defined to begin at 8000 ft above sea level (Chamberlin, 2015).

Fig. 1.1 Percentage of oxygen at different altitudes.

Generally, prolonged stay at high altitudes as a part of adventure sport or country's defense means living in stressful environment leading to a need to study the effects of such an alien locale. The most significant and connatural factor of high altitudes is hypoxia. Hypoxia or rarefied atmosphere with low oxygen availability affects both physical and mental performances of people because oxygen is even more essential to life than food and water.

This chapter introduces readers to the concepts of high altitudes, the worldwide scenario of high altitudes, and the related hypoxia (i.e., hypobaric hypoxia). This basic knowledge is essential for better understanding of high-altitude pathophysiologies and their management.

1.2 High Altitudes: Worldwide Scenario

High altitudes of mountains have always been a source of great fascination and inspiration for people. The serenity and calmness of mountains allure thinkers, spiritualists, and philosophers; the exigent environment challenges mountaineers, and unexplored resources lure people to inhabit areas of even higher reaches of mountains. Establishment of a major civilization in the Himalayan region (3500–4500 m) is a well-known example of successful adaptation to high altitude (Aldenderfer, 2003; Shi et al., 2008; Wu, 2001; Yuan et al., 2007; Zhao et al., 2009). A large population also lives at 4500 m in the Peruvian Andes, and caretakers of a mine in Chile have lived at nearly 6000 m. Lhasa, in Tibet, altitude 3658 m, has more than 130,000 inhabitants. The highest point on Earth is the summit of Mt. Everest (8848 m), and well-acclimatized climbers can just reach that altitude without oxygen (Encyclopedia.com, 2001).

1.3 High Altitudes Environment and Hypoxia

The mountain environment is composed of several factors that are alien to plain dwellers and therefore evokes modifications in the physiology and homeostasis. The most crucial and inherent factors of such an environment are hypoxia (lack of oxygen because of thinning of air), cold (for every 150 m rise, the temperature drops 1°C), wind (adds to the effect to cold leading to chill), increased solar radiation, ozone concentration, absence of flora and fauna, isolation from civilization. Individually, these factors are potent psycho-physiological stress-producing elements. When they exist together in variable proportions in different geographical locations and seasons they evoke an alarming challenge to human adaptability and capacity to survive. Hypoxia, however, remains the primary factor defining all other stress factors. At high altitude, it arises because atmospheric pressure is lower than that at sea level. This situation exists because of two physical effects: gravity, which causes the air to be as close to the ground as possible; and the heat content of the air, which causes the molecules to bounce off each other and expand (Hackett and Roach, 2001). High-altitude hypoxia persistently affects people living in this environment because oxygen is even more essential to life than food and water (Julian et al., 2009).

1.3.1 Defining the Term Hypoxia

Van Liere and Stickney (1963) wrote a book about hypoxia in which they described anoxemia as deficiency of oxygen in the blood (Van Liere and Stickney, 1963). Other scientists, however, proposed that body suffers deficiency in oxygen even though there is no deficiency in the blood. For such conditions, Barcroft (1920) suggested the term anoxia, a condition of oxygen deprivation in the body regardless of the cause. In his studies, he identified three types of anoxia: anoxic, anemic, and stagnant (Barcroft, 1920). The term anoxia, however, also was objected to because it actually meant without oxygen/or total lack of oxygen, a condition that does not exist. Sometimes, hypoxia is confused with another term, asphyxia. It should be clearly understood that in asphyxia, carbon dioxide accumulates in the body's lungs and tissues. The most acceptable term was determined to be hypoxia [hypo = a Greek word meaning under/sub and oxygen] that means less than a normal amount of oxygen. This is summarized in Fig. 1.2. Hypoxia can be combined with the terms normobaric, hypobaric, stagnant, anoxic, anemic, and histotoxic to express the exact type of oxygen deficiency.

Fig. 1.2 Origin of the term hypoxia.

1.3.2 Types of Hypoxia

Various researchers describe the different types of hypoxia depending on the type of oxygen deficiency (Van Liere and Stickney, 1963; Millet et al., 2012).

Normobaric hypoxia: When there is reduction in inspired fraction of oxygen below 20% although the barometric pressure remains at 760 mmHg.

Hypobaric hypoxia: When the body is deprived of a sufficient supply of oxygen from the air to supply the body tissues whether in quantity or molecular concentration.

Anoxic hypoxia: When there is lack of oxygen in arterial blood that leads to unsaturation of hemoglobin to its normal extent; sometimes called hypoxemia or arterial hypoxia.

Anemic hypoxia: When oxygen tension (partial pressure of oxygen) in arterial blood (normally 75–100 mmHg) is sufficient but it cannot be carried because of lack of functional hemoglobin.

Stagnant hypoxia: When arterial blood holds a normal amount of oxygen under normal tension but it is not given off to the tissues; arises because of insufficient supply of blood in capillaries because of some heart problem.

Histotoxic hypoxia: When the tissues are unable to use the oxygen that is supplied to it as happens in cyanide poisoning.

1.4 Hypobaric Hypoxia and Physiology

One of the major stresses faced at high altitudes is hypobaric hypoxia, which occurs as the direct result of the nearly exponential fall in barometric pressure as one ascends from sea level. Because the relative concentration of oxygen in the troposphere (lowest atmospheric layer) is constant at 20.93%, the partial pressure of oxygen in ambient air (PO2) for a given elevation is obtained by multiplying 0.2093 by the corresponding barometric pressure. At sea level, PO2 is 0.2093 multiplied by 760 mmHg, or 159.1 mmHg. At the summit of Mt. Everest, the ambient PO2 is only 52.9 mmHg. Such low pressures of oxygen (hypoxia) result in stress-related ailments (Hackett and Roach, 2001; Schoene, 2001). In the next chapter, we will discuss these ailments, their causes, and effects.

1.5 Conclusion

This chapter introduced the readers to the concepts of high altitudes, the worldwide scenario of high altitudes, and the related hypoxia (i.e., hypobaric hypoxia). This chapter is crucial for better comprehension of high-altitude associated pathophysiologies and the various approaches applied or applicable for their management.

References

Aldenderfer M.S. Moving up in the world: archaeologists seek to understand how and when people came to occupy the Andean and Tibetan plateaus. Am. Sci. 2003;91(6):542–550.

Barcroft J. On anoxaemia. Lancet. 1920;2(4):485.

Chamberlin, R., 2015. Survival medicine tips techniques & secrets. The Prepper Pages.com. February 4th 2015. Available from: https://www.prepperwebsite.com/. A survival medicine & medical preparedness blog sharing tips, techniques and secrets for building the perfect first aid kit and using it to treat injuries and illnesses preppers encounter during disasters (accessed 23 October 2017).

Encyclopedia.com. Altitude facts, information, pictures. Encyclopedia.com articles about altitude. Available from: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/altitude. 2001.

Hackett P.H., Roach R.C. High-altitude illness. N. Engl. J. Med. 2001;345(2):107–114.

ISO 6709:2008(en) preview. www.iso.org. ISO. 2008. Retrieved 8 June 2016.

Julian C.G., Wilson M.J., Moore L.G. Evolutionary adaptation to high altitude: a view from in utero. Am. J. Hum. Biol. 2009;21(5):614–622.

Millet G.P., Faiss R., Pialoux V. Point/counterpoint: hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia. J. Appl. Physiol. 2012;112(10):1783–1784.

Schoene R.B. Limits of human lung function at high altitude. J. Exp. Biol. 2001;204(18):3121–3127.

Shi H., Zhong H., Peng Y., Dong Y.L., Qi X.B., Zhang F., Liu L.F., Tan S.J., Ma R.Z., Xiao C.J., Wells R.S. Y chromosome evidence of earliest modern human settlement in East Asia and multiple origins of Tibetan and Japanese populations. BMC Biol. 2008;6(1):45.

Van Liere E.J., Stickney J.C. Hypoxia. Library of Congress Catalog Card Number: 63-16722. Chicago and London: The University of Chicago Press; 1963.

Wu T. The Qinghai–Tibetan plateau: how high do Tibetans live? High Alt. Med. Biol. 2001;2(4):489–499.

Yuan B., Huang W., Zhang D. New evidence for human occupation of the northern Tibetan plateau, China, during the late Pleistocene. Chin. Sci. Bull. 2007;52(19):2675–2679.

Zhao M., Kong Q.P., Wang H.W., Peng M.S., Xie X.D., Wang W.Z., Jiayang, Duan J.G., Cai M.C., Zhao S.N., Cidanpingcuo, Tu Y.Q., Wu S.F., Yao Y.G., Bandelt H.J., Zhang Y.P. Mitochondrial genome evidence reveals successful late Paleolithic settlement on the Tibetan plateau. Proc. Natl. Acad. Sci. U. S. A. 2009;106:21230–21235.

Chapter 2

High Altitude Ailments: Causes and Effects

Shefali Gola⁎; Kshipra Misra†    ⁎ Department of Basic and Applied Sciences, School of Engineering, GD Goenka University, Haryana, India

† Department of Biochemical Sciences (DBCS), Defence Institute of Physiology and Allied Sciences (DIPAS), Delhi, India

Abstract

More than 100 million people visit high-altitude (HA) locations (up to 2500 m and higher) annually for recreation and adventure purposes, testing the limits of human endurance. HA is characterized chiefly by several adverse environmental conditions such as low barometric pressure, low air humidity, and low atmospheric temperature, high aridity, high ultraviolet radiation, and, most prominently, hypobaric hypoxia. At HA, most of the undesirable physiological effects result from the decrease in atmospheric pressure and low availability of oxygen, additional deterioration results from extreme cold, exposure to ionizing, and high wind velocity. Exposure to these environmental stresses at HA commences an intricate sequence of pathophysiological effects. Hypobaric hypoxia is a major concern because it tends to cause a wide range of physiological HA illnesses, including acute mountain sickness (AMS), sleep disturbance, HA retinopathy, hypophagia, and life-threatening pathophysiological ailments such as high-altitude cerebral edema and high-altitude pulmonary edema.

Keywords

High altitude; Hypoxia; AMS; HACE; HAPE; Sleep disturbance; High-altitude retinopathy

Abbreviations

AMS 

acute mountain sickness

ENaCs 

epithelial sodium channels

EPO 

erythropoietin

Erg-1 

ETS-related gene-1

GAPDH 

glyceraldehyde phosphate dehydrogenase

HA 

high altitudes

HACE 

high-altitude cerebral edema

HAPE 

high-altitude pulmonary edema

HIF 

hypoxia-inducible factor

HPV 

hypoxic pulmonary vasoconstriction

NF-κB 

nuclear Factor Kappa B

NSAIDs 

nonsteroidal antiinflammatory drugs

PaO2 

arterial partial pressure of oxygen

PiO2 

partial pressure of inspired O2

PO2 

pressure of oxygen

p53 

tumor protein p53

RNFL 

retinal nerve fiber layer

VEGF 

vascular endothelial growth factor

Acknowledgments

The authors are thankful to the vice chancellor of GD Goenka University, Gurgaon, Haryana, India, and the director of Defense Institute of Physiology and Allied Sciences, Delhi, India, for their constant support and encouragement.

2.1 Introduction

The association of humans with the mountains is almost as old as mankind. Mountain ranges comprise approximately one-fifth of Earth's land surface and all are inhabited to some extent. About one-tenth of the world's people derive their life support from mountains. In spite of long strides on scientific and technological fronts, the challenges offered by high-altitude (HA) conditions remain to be overcome. The misty weather and distant high peaks attract people and promise great adventure. Millions of people sojourn to HA each year for recreation and adventure purposes and test the limits of human endurance. The numbers of mountaineers, rescue teams, defense personnel, and natives who travel to extreme HA regions, especially Alps in Europe, Himalayas in Asia, Andes in South America, and Rockies in the United States, have increased enormously in the past decades (Peacock, 1998). Understanding the physiological effects of HA exposure and discovering how to ameliorate these effects is of chief importance for securing the health and livelihood of the large number of humans subjected to these stressful environmental conditions.

HA ranges from intermediate altitude (1500–2500 m), high altitude (2500–3500 m), very high altitude (3500–5800 m), to extreme altitude (> 5800 m). It is deemed that human life is not possible above 5500 m permanently, although moderate altitudes sometimes can be tolerated without supplementary oxygen (Hackett, 1999a; Hackett and Roach, 2001a). HA is chiefly characterized by several adverse environmental conditions, including low barometric pressure, low air humidity, low atmospheric temperature, high aridity, high ultraviolet radiation, and, most prominently, hypobaric hypoxia. At HA, most of the undesirable physiological effects result from the decrease in atmospheric pressure and low availability of oxygen, additional deterioration results from extreme cold, exposure to ionizing radiation, and high wind velocity. The unenviable pathophysiologies encountered at HA are discussed in subsequent sections.

2.1.1 Hypobaric Hypoxia at High Altitudes

The main environmental stress at HA is hypobaric hypoxia, which is caused by the fall in barometric pressure with increasing altitude and the fewer oxygen molecules in a breath of air as compared with sea level. Although oxygen availability in air is 21% at any altitude, the partial pressure and thus the bioavailability of oxygen decreases with altitude, causing a condition called hypobaric hypoxia. The decreased barometric pressure of the ambient atmosphere at HA results in diminished alveolar oxygen tension and, as a result, arterial partial pressure of oxygen (PaO2) falls significantly (Fedele et al., 2002). Reduced oxygen partial pressure causes the arterial hemoglobin to be inadequately saturated with oxygen (Peacock and Jones, 1997), resulting in hypoxia that not only limits human physical performance (Pugh, 1964; West, 1988) but also brings out many physiological changes and putting the body in further jeopardy. For example, at the altitude of La Paz, Bolivia (4000 m), partial pressure of inspired O2 (PiO2) is 86.4 mm Hg, which is equivalent to breathing 12% oxygen at sea level. The decrease in PaO2 is the most significant environmental change caused by HA; therefore, HA environment commonly is referred to as one of hypobaric hypoxia. The ascent rate and period of stay at HA greatly influence the effects of hypobaric hypoxia. These effects progressively become more intense with increasing altitude and period of stay, thus stressing the biological systems (Fedele et al., 2002).

2.1.2 Physiological Adaptations at High Altitudes: The Acclimatization Process

An organism's survival often depends on its ability to acclimatize to environmental stresses. A typical example of adaptation to a stressful environment is acclimatization to HA. The process of acclimatization allows the gradual adjustment of individuals to hypoxia and enhance their survival and performance under hypoxia (Paralikar and Paralikar, 2010). On ascent to HA, the oxygen cascade in human body get disrupted. Acclimatization to hypoxic condition involves several organ systems and tissues of the human body. These physiological responses commence after ascent to an altitude of about 1500 m, generally within the first few minutes to hours. The onset of HA-induced hypoxia triggers an immediate rise in alveolar ventilation, which is regulated by carotid body, causing an increase in arterial oxygen content. Physiological effects observed at HA include increased production of hemoglobin along with increase in hematocrit and oxygen-carrying capacity of blood; elevated 2,3-bisphosphoglycerate production; pulmonary vasoconstriction; raised mass of lung and liver; increased mass of left ventricle; elevated tidal volume and rate of ventilation; increased capillary density; anorexia and subsequent weight loss (Aaron and Powell, 1993; Benjamini and Hochberg, 1995; Branco et al., 2006; Gopfert et al., 1996; Mortola, 1999; Shukla et al., 2005). Furthermore, while the above physiological changes are proceeding, body alters its metabolic capacity to reduce the oxygen requirement. This involves elevated anaerobic glycolysis and glucose consumption, decreased rate of metabolism, and decrease in body temperature (Gautier, 1996; Hochachka et al., 1996; Semenza et al., 1994; Steiner and Branco, 2002).

Substantial information is available about the physiological acclimatization to hypoxic exposure, however, some studies have focused primarily on the changes involving principal molecular genetics. Several studies about the effects of hypoxia on genes and protein expressions have focused on the responses of cells to hypoxia exposure. Alterations in transcription factors, such as nuclear factor kappa B (NF-κB), tumor protein p53 (p53), AP-1, Myc family of proteins and ETS-related gene-1 (Erg-1), take place in response to cellular hypoxia. These transcription factors play a crucial role in the processes of cell development regulation, cell proliferation and differentiation, inflammation and apoptosis, and respond to various stressors (Cummins and Taylor, 2005; Kenneth and Rocha, 2008). One of the transcription factors that respond to hypoxic exposure is hypoxia-inducible factor (HIF). Under hypoxic conditions, the HIF-1α subunit accumulates rapidly and dimerizes with the HIF-1β subunit, leading to the transcription of more than 70 hypoxia responsive genes (Hammond et al., 2002; Haouzi et al., 2008; Jungermann and Kietzmann, 2000). Many of these genes are linked with various physiological changes caused by hypoxia (Sarkar et al., 2003). For example, under hypoxic conditions, HIF triggers upregulation of erythropoietin (EPO), transferrin, genes related with angiogenesis, such as vascular endothelial growth factor (VEGF), and genes linked with various metabolic substrates, such as glyceraldehyde phosphate dehydrogenase (GAPDH) and pyruvate kinase, which enhance the uptake of glucose and anaerobic glycolysis (Bracken et al., 2003; Semenza, 2000). An insufficiency of HIF-1α, however, hinders long-term physiological responses to hypoxia. Therefore, both responses and physiological acclimatization to hypoxia are controlled immensely by the HIF pathway (Aimee et al., 1999).

2.1.3 Physical Factors at High Altitudes

In addition to hypoxia, HA also is characterized by cold ambient temperatures, increased UV radiation, and high wind velocity. The physical and mental performance at HA is highly affected by these physical and physiological stresses as well as such as dehydration and lack of antioxidant nutrients in the diet (Askew, 1995; Cymerman, 1996; Huey and Eguskitza, 2001).

2.2 High-Altitude Ailments

Altitude exposure and acclimatization long have been areas of research. The immediate (acute) effects of lowered ambient pressure of oxygen (PO2) pertaining to the human response and the adaptations to prolonged exposure (chronic) are complex. Several body systems (i.e., muscular, cardiovascular, pulmonary, endocrine, hepatic) are affected by HA-induced hypoxia. High-altitude ailments represent physiological alterations associated with environmental challenges imposed by hypobaric hypoxia.

The term HA ailments or sickness is used mainly for a class of pathophysiological conditions caused by rapid ascent to HA of above 2500 m (Litch, 2007). The three main types of altitude sickness are acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) (Basnyat, 2005; Chao et al., 1999; Fiore et al., 2010; Hartman-Ksycińska et al., 2016; Khodaee et al., 2016; Luks, 2015; Luks et al., 2017; Parise, 2017; Singh and Selvamurthy, 1993; Smedley and Grocott, 2013). Unacclimatized sojourners are at high risk from HA conditions. Cerebral and pulmonary anomalies are not subtle, and might lead to death if unrecognized or ignored. The various risk factors that are general to all altitude sicknesses are the absolute altitude, the speed of ascent, individual predisposition, and lack of acclimatization (Schneider et al., 2002) (Table 2.1).

Table 2.1

Adapted from Fiore, D.C., Hall, S., Shoja, P., 2010. Altitude illness: risk factors, prevention, presentation, and treatment. Am. Family Phys. 82(9), 1103–1110; McFadden, D.M., Houston, C.S., Sutton, J.R., Powles, A.P., Gray, G.W., Roberts, R.S., 1981. High-altitude retinopathy. JAMA 245(6), 581–586; Paralikar, S.J., Paralikar, J.H., 2010. High-altitude medicine. Ind. J. Occupat. Environ. Med. 14(1), 6–12; Parise, I., 2017. Travelling safely to places at high altitude—understanding and preventing altitude illness. Aust. Family Phys. 46(6), 380–384; Rennie, D., Morrissey, J., 1975. Retinal changes in Himalayan climbers. Arch. Ophthalmol. 93(6), 395–400; Schoene, R.B., 2008. Illnesses at high altitude. Chest 134(2), 402–416; Weil, J.V., 2004. Sleep at high altitude. High Alt. Med. Biol. 5(2), 180–189.

2.2.1 Acute Mountain Sickness

Altitude sickness, also known as acute mountain sickness (AMS), altitude illness, hypobaropathy, or soroche, is a pathological effect of HA on humans. AMS might progress to HAPE or HACE, which are potentially